Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions

• Published in: PloS one Vol. 10; no. 10; p. e0139853
• Main Authors: Kalus, Ina, Rohn, Susanne, Puvirajesinghe, Tania M, Guimond, Scott E, Eyckerman-Kölln, Pieter J, Ten Dam, Gerdy, van Kuppevelt, Toin H, Turnbull, Jeremy E, Dierks, Thomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.10.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antigenic determinants; Apoptosis; Axonogenesis; Biochemical analysis; Brain; Cell adhesion & migration; Cell Movement - drug effects; Cell surface; Cell survival; Cell Survival - drug effects; Cells, Cultured; Cerebellum; Cerebellum - cytology; Cerebellum - metabolism; Development Biology; Embryology and Organogenesis; Epitopes; Female; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Granule cells; Hedgehog Proteins - pharmacology; Heparan sulfate; Heparan Sulfate Proteoglycans - metabolism; Life Sciences; Localization; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Neonates; Nerve growth factor; Nerve Growth Factor - pharmacology; Neurites - drug effects; Neurites - physiology; Neurobiology; Neurons; Neurons - metabolism; Neurons and Cognition; Neuroprotection; Precursors; Proteoglycans; Rodents; Signal Transduction; Signaling; Sulfatases - deficiency; Sulfatases - genetics; Sulfatases - metabolism; Sulfates; Sulfation; Sulfotransferases - deficiency; Sulfotransferases - genetics; Sulfotransferases - metabolism; Survival; United States; United Kingdom > UK; Netherlands; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139853

Sulf1 and Sulf2 are cell surface sulfatases, which remove specific 6-O-sulfate groups from heparan sulfate (HS) proteoglycans, resulting in modulation of various HS-dependent signaling pathways. Both Sulf1 and Sulf2 knockout mice show impairments in brain development and neurite outgrowth deficits in neurons. To analyze the molecular mechanisms behind these impairments we focused on the postnatal cerebellum, whose development is mainly characterized by proliferation, migration, and neurite outgrowth processes of precursor neurons. Primary cerebellar granule cells isolated from Sulf1 or Sulf2 deficient newborns are characterized by a reduction in neurite length and cell survival. Furthermore, Sulf1 deficiency leads to a reduced migration capacity. The observed impairments in cell survival and neurite outgrowth could be correlated to Sulf-specific interference with signaling pathways, as shown for FGF2, GDNF and NGF. In contrast, signaling of Shh, which determines the laminar organization of the cerebellar cortex, was not influenced in either Sulf1 or Sulf2 knockouts. Biochemical analysis of cerebellar HS demonstrated, for the first time in vivo, Sulf-specific changes of 6-O-, 2-O- and N-sulfation in the knockouts. Changes of a particular HS epitope were found on the surface of Sulf2-deficient cerebellar neurons. This epitope showed a restricted localization to the inner half of the external granular layer of the postnatal cerebellum, where precursor cells undergo final maturation to form synaptic contacts. Sulfs introduce dynamic changes in HS proteoglycan sulfation patterns of the postnatal cerebellum, thereby orchestrating fundamental mechanisms underlying brain development.